DESCRIPTION: The first three years of the project included studies to understand how experimental manipulations of the hippocampus or medial prefrontal cortex (MPFC) in rats produce deficits in basic gating and habituation functions that are linked to schizophrenia. Both prepulse inhibition (PPI) and habituation of startle responses have been used to demonstrate gating and habituation deficits in schizophrenia patients and in rats with altered cortico-striatal circuitry. The ventral hippocampus (VH) and MPFC appear to modulate startle inhibitory processes via connections with the nucleus accumbens (NAC). Rats with VH or MPFC lesions exhibit an enhanced sensitivity to the PPI-disruptive effects of dopamine (DA) agonists. This proposal seeks continued support to test specific hypotheses about neural circuitry that is implicated in the pathophysiology of schizophrenia, and to understand the role of this circuitry in schizophrenia-linked gating deficits. Aim 1 will assess the importance of VH lesions (excitotoxic and electrolytic) versus NAC de-efferentation in the development of the enhanced DA-mediated loss of sensorimotor gating, using septal undercuts to interrupt the rostral fornix. To enhance our understanding of the neurochemical basis for the effects VH lesions on PPI, studies will also assess changes in the PPI-disruptive effects of NMDA antagonists and 5HT agonists after VH lesions, and the PPI-restorative effects of antipsychotics. Aim 2 will assess the neural basis for VH lesion effects on PPI, by measuring changes in PPI after DA infusions into NAC subregions. Studies will also test the hypothesis that the effects of VH lesions on PPI are accompanied by changes in DAergic substrates in the MPFC or orbital cortex. Aim 3 will examine the ability of glutamatergic manipulations of the NAC, or transection of the VH-NAC projection, to reverse the PPI-disruptive effects of intra-VH infusion of NMDA. Aim 4 will assess the enhanced DA-mediated loss of PPI after cell or ablative lesions of the MPFC, across post-lesion intervals and via DA receptor subtype-specific agonists, and with measures of forebrain DA receptors. Aim 5 will examine MPFC lesion-induced changes in PPI after infusion of DA agonist into NAC subregions. Aim 6 will test the ability of manipulations of the NAC or ventral tegmentum to reverse the PPI-disruptive effects of MPFC 6-OHDA lesions or intra-MPFC infusion of DA antagonists. In total, these studies will systematically characterize cortico-striatal circuitry regulating critical inhibitory functions that are deficient in schizophrenia. Specific circuit mechanisms responsible for DA-mediated gating deficits after VH or MPFC lesions - revealed by these studies - will continue to be the basis for innovative models of the pathophysiology of schizophrenia and related disorders, and for prospective strategies for novel drug development.